Recent developments in molecular genetics promise to help elucidate the etiology and pathophysiology of drug abuse/dependence. Much interest has been generated by the report of an association between alcoholism and a restriction fragment length polymorphism at the D2 dopamine receptor gene (DRD2). However, that association is controversial, since a number of studies have failed to replicate it, raising the question of whether population stratification (i.e., sampling bias) may have produced a false-positive result. Although a similar association of DRD2 alleles has been reported for drug dependence, our study of cocaine abusers did not replicate that finding. The present Exploratory/Developmental application (R21) will use the haplotype relative risk (HRR) method (Falk and Rubenstein 1987) in an effort to avoid population stratification, while testing the hypothesized association between DRD2 alleles and drug abuse. The HRR method controls for variation in allele frequency that can result from biased selection by constructing a control group of nontransmitted parental alleles. The method will be used to study the association of DRD2 alleles in two groups of drug abusers (100 cocaine abusers and 100 opiate abusers), each of which will include comparable numbers of males and females and blacks and whites. All biological parents and affected biological siblings of these probands will also be clinically assessed and genotyped. In addition to applying the HRR method in an effort to help resolve the controversy over the association of DRD2 alleles and drug abuse, the feasibility of the sib-pair method to test for genetic linkage and a cluster analytic approach to phenotyping will be evaluated. Finally, the clinical data and DNA collected will also make it possible to test association and-linkage between drug abuse and a variety of other candidate genes.